Endopeptidase 24.11, which is one of neutral endopeptidases, is a metal-containing neutral peptidase which is required to contain zinc in its active center and it is also called enkephalinase or an antigen of acute lymphoblast leukemia (CD10).
Endopeptidase 24.11 is an enzyme which distributes widely, for example, in the kidney, lungs, central nervous system, the intestinal canal, neutrophil, fibroblast, vascular endothelial cells, etc. and hydrolyzes various physiologically active peptides such as artial natriuretic polypeptide (ANP), enkephaline, bradykinin and substance P. Accordingly, the enzyme is known to take part in various biofunctions and to exhibit various therapeutic effects by inhibiting the above-mentioned enzymatic activity.
These effects are exemplified by an effect on cardiovascular diseases such as heart failure indicating symptoms of edema and hypertension, an effect on renal diseases such as renal failure indicating symptom of edema or an increase of ascites, an effect on gastroenteric disorders such as diarrhea and hyperchlorhydria, an analgestic effect, an effect on endocrine and metabolic diseases such as obesity, and an effect on autoimmune diseases such as rheumatic disease.
Substances inhibiting endopeptidase 24.11 are described below in more detail.
The following effects of compounds inhibiting endopeptidase 24.11 have been observed. An increasing effect of total urine volume and urinary sodium excretion has been observed on heart failure models by rapid ventricular pacing method (J. Cardiovasc. Pharmacol., 19, 635-640 (1992)). An increasing effect of urinary ANP excretion and urinary cyclic GMP excretion has been observed (J. Pharmacol. Exp. Ther., 266, 872-883 (1993)). A hypotensive effect has been observed using spontaneously hypertensive rats or deoxycorticosteron acetate induced hypertensive rats (J. Pharmacol. Exp. Ther., 265, 1339-1347 (1993)). An increasing effect of urinary sodium excretion has been observed using rats subjected to five-sixths renal ablation (Circ. Res., 65, 640-646 (1989)). An inhibitory effect, which is derived from the effect on the central nervous system, upon pentagastrin-stimulated gastric secretion has been observed (Eur. J. Pharmacol., 154, 247-254 (1988)). An improvement effect of acute diarrhea caused by castor oil has been observed (Gut, 33, 753-758 (1992)). An analgestic effect has been observed by the tail-withdrawal test and the hotplate jump test (Nature, 288, 286-288 (1980)). In addition, since bonbesin (Proc. Natl. Acad. Sci., 88, 10662-10666 (1991)), which is known as one of substrates of endopeptidase 24.11, has been reported to reduce food intake (J. Clin. Endocrinol. Metab., 76, 1495-1498 (1993)), a compound inhibiting endopeptidase 24.11 is expected to be a therapeutic agent for endocrine and metabolic disease such as obesity. Since an endopeptidase 24.11 activity in blood and synovial fluid has been reported to be higher in patients with rheumatoid arthritis than in healthy men and patients with osteoarthritis (Rheumatol. Int., 13,1-4 (1993)), a compound inhibiting endopeptidase 24.11 is expected to be a therapeutic agent for autoimmune disease where an immune function is lowered such as rheumatic disease.
On the other hand, a structural feature of the present invention is that carboxyl group(s) and/or phosphonic group(s) are introduced into each terminal end of both alkylene chains of 1,3-dialkylurea and further a group wherein a plurality of aromatic monocyclic hydrocarbons are combined or condensed, such as biphenylyl group and naphthyl group is introduced into the alkylene chains. Prior art is described below from the standpoint of the chemical structure.
It has been reported that 1,3-dialkylurea derivatives wherein a carboxyl group is introduced at the end of one alkylene chain have angiotensin II antagonistic effect (Laid-open Japanese Patent Publication Nos. 6-72985 and 6-184086). It has been reported that 1,3-dialkylurea derivatives wherein carboxyl groups are introduced at the ends of both alkylene chains inhibit an angiotensin-converting enzyme (Laid-open Japanese Patent Publication No. 58-55451). It has also been reported that amino acid derivatives containing a nitrogen atom located at the 3rd position of 1-(carboxyalkylamino)urea derivatives inhibit an activity of enkephalinase (Examined Japanese Patent Publication No. 3-79339). However, none of them disclose a compound wherein a biphenyl group or a naphthyl group is introduced into an alkylene chain of a 1,3-dialkylurea derivative.
It is reported that an alkylurea derivative containing a biphenylyl group or a naphthyl group can be used as an agent for inhibiting allergy (Laid-open Japanese Patent Publication No. 62-294650) and a bronchodilator (U.S. Pat. No. 5,066,658). It is also reported that a compound wherein a terminal end of an alkylene chain is a hydroxamic group inhibits biosynthesis of leukotriene because it has a lipoxygenase inhibition activity (WO90/08545). It is also reported that an analogue of a luteinizing hormone releasing hormone controls a level of a sex hormone (Laid-open Japanese Patent Publication No. 3-81292). However, none of them disclose a compound wherein carboxyl group(s) and/or phosphonic group(s) are introduced into each terminal end of both alkylene chains of a 1,3-dialkylurea derivative having a biphenylyl group or a naphthyl group.
As mentioned above, various studies have been made for the 1,3-dialkylurea derivatives, but there has never been studied about an urea derivative wherein carboxyl group(s) and/or phosphonic group(s) are introduced into each terminal end of both alkylene chains and, furthermore, a group wherein a plurality of aromatic monocyclic hydrocarbons are combined or condensed is introduced into one alkylene group. It was a very interesting subject to synthesize such compounds and to examine their pharmacological effects, particularly their effects on endopeptidase 24.11.
The present inventors have paid attention to the alkylene chains of the 1,3-dialkylurea derivative, synthesized a novel urea derivative wherein carboxyl group(s) and/or phosphonic group(s) are introduced into each terminal end of both alkylene chains and, furthermore, a group wherein a plurality of aromatic monocyclic hydrocarbons are combined or condensed is introduced into one alkylene group and then studied about the pharmacological effects thereof.
As a result of the study using N-dansyl-D-alanyl-glycyl-p-nitrophenylalanyl-glycine, which is known as a substrate of endopeptidase 24.11, it has been found that the novel urea derivatives wherein carboxyl group(s) and/or phosphonic group(s) are introduced into each terminal end of both alkylene chains and, furthermore, a group wherein a plurality of aromatic monocyclic hydrocarbons are combined or condensed is introduced into one alkylene group have high inhibitory activities to endopeptidase 24.11.